Abstract
ABSTRACT Background Interleukin 6 (IL-6), one of the proinflammatory cytokines, contributes to the onset and maintenance of various types of cancer. IL-6 signaling induces up-regulation of SOCS3, which leads to interferon (IFN) –α resistance in renal cell carcinoma (RCC) cells. To propose a new treatment for mRCC, we investigated the effect of combination therapy with IFN-α and humanized antihuman IL-6R antibody, tocilizumab. Material and methods Real time PCR (RT-PCR) was used to analyze gene expression of IL-6 and SOCS3 after IFN stimulation and ELISA were used for IL-6 secretion in RCC cell lines. These expression levels were compared among the RCC cell lines, i.e., ACHN, Caki-1, TUHR3TKB, TUHR4TKB and 786-O. Phosphorylation of STAT-1, STAT-3 and ERK were investigated by Western blotting (WB) analysis. We investigated alteration of IL-6 signaling by tocilizumab, and analyzed its impacts on the susceptibility to IFN-α in RCC cells by MTT assay. The effects of tocilizumab on in vivo growth on 786-O xenografts were determined by SOCS3 expression, morphological observation and tumor volume. Results Among the RCC cell lines, the expression levels of IL-6, SOCS3 in RT-PCR and the production level of IL-6 were highest in 786-O. These results revealed a correlation between the expression levels IL-6 and SOCS3 (P = 0.0001, r = 0.99974). Although the 786-O cells had IFN-α resistance, MTT assay showed that the tocilizumab induced a growth inhibitory effect of IFN-α. WB analysis showed that phosphorylation level of STAT-1 was increased and the levels of STAT-3 and ERK were decreased with the simultaneous use of tocilizumab in 786-O cells. An in vivo study demonstrated that tocilizumab promoted IFN-α-induced cell death and growth suppression in 786-O cell xenograft in nude mice. Conclusions IL-6 could be a key component in the resistance to IFN-α treatment of renal cell carcinoma. Antihuman IL-6R antibody can be an effective strategy to enhance the anti-tumor effect of IFN-α, and probably, the effect of angiogenic inhibitors, in human RCC cells. Disclosure All authors have declared no conflicts of interest.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
